Summary Safety Review - Dipeptidylpeptidase-4 (DPP-4) Inhibitors - Assessing the Potential Risk of Heart Failure

June 15, 2017

Product

DPP-4 inhibitors (gliptins): alogliptin, saxagliptin, sitagliptin and linagliptin

Potential Safety Issue

Heart failure

Key Messages

• DPP-4 inhibitors, also known as gliptins, are prescription drugs authorized for sale in Canada to treat type 2 diabetes in adults.
• Health Canada reviewed the increased potential risk of heart failure with the use of these products as a follow-up to a risk communication released by the United States Food and Drug Administration (U.S. FDA) stating that saxagliptin and alogliptin might increase the risk of heart failure, in particular in patients who have other risk factors for heart failure. Health Canada’s review included all DPP-4 inhibitors available in Canada.
• While Health Canada was carrying out the review, the manufacturers of DPP-4 inhibitors updated the product safety information to include information regarding the potential risk of heart failure. Health Canada's review of the available information concluded that the recently updated product safety information for DPP-4 inhibitors accurately describes the potential risk of heart failure when using these products. Health Canada will continue to monitor the safety of DPP-4 inhibitors.

Overview

A safety review was carried out by Health Canada to evaluate the increased risk of heart failure with the use of DPP-4 inhibitors as a follow-up to a risk communication released by the U.S. FDA stating that saxagliptin and alogliptin might increase the risk of heart failure, in particular in patients who have other risk factors for heart failure. The product safety information in the U.S. and Canada were recently updated to include this risk.

In Canada, the product safety information for the 4 different gliptins on the Canadian market (sitagliptin, saxagliptin, alogliptin and linagliptin) currently discusses the risks of using these products in patients with a history of congestive heart failure.

Use in Canada

• DPP-4 inhibitors, also known as gliptins, are prescription drugs authorized for sale in Canada to treat type 2 diabetes in adults. They are used along with an appropriate diet and exercise to control blood sugar. In some cases, they are used with another anti-diabetic drug.
• There are currently 4 different gliptins on the Canadian market: sitagliptin, saxagliptin, linagliptin and alogliptin. These drugs are also available in products that combine them with other drugs that treat type 2 diabetes.
• Sitagliptin was the first gliptin sold in Canada in 2008. There were around 4.8 million prescriptions for DPP-4 inhibitors in 2015.

Safety Review Findings

• At the time of the review, Health Canada received 9 Canadian reports^{Footnote a} of heart failure where DPP-4 inhibitors were used, and in 8 of these reports, there was a possible link between the use of a DPP-4 inhibitor and heart failure (5 with sitagliptin, 2 with saxagliptin and 1 with linagliptin). However, these 8 reports included other factors that may have contributed to heart failure. This made it difficult to know the role of DPP-4 inhibitors in these reports of heart failure, especially since heart failure happens more often in diabetics than in people who are not diabetic.
• In 2008, the U.S. FDA asked the manufacturers of all antidiabetic drugs (including DPP-4 inhibitors) to do more safety studies to assess the risks linked to problems of the heart and blood vessels (cardiovascular events). Studies for 3 DPP-4 inhibitors (sitagliptin, saxagliptin and alogliptin) have been completed and reviewed by Health Canada, while the studies for linagliptin will be completed in 2019.  The results of the 3 completed safety studies do not agree with each other on the increased risk of hospitalization due to heart failure in patients treated with DPP-4 inhibitors. Some studies found a link while others did not. The results from these 3 completed safety studies have been added to the product safety information for sitagliptin (October 2016), saxagliptin (August 2016) and alogliptin (April 2016).
• Health Canada reviewed 7 publications that combine the results of many studies (meta-analyses) that looked at the increased risk of heart failure in patients treated with DPP-4 inhibitors.  Some authors found a link, while others did not. Most of the clinical trials did not, or could not, separate the risk associated with each DPP-4 inhibitor, so it is not possible to tell if there is a difference in the risk between the different DPP-4 inhibitors.

Conclusions and Actions

• While Health Canada was carrying out the review, the manufacturers of DPP-4 inhibitors updated the product safety information to include information regarding the potential risk of heart failure. Health Canada's review of the available information concluded that the recently updated product safety information for DPP-4 inhibitors accurately describes the potential risk of heart failure when using these products.
• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of these health products.
• Health Canada will continue to monitor safety information involving DPP-4 inhibitors, as it does for all health products on the Canadian market, in order to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports and what is known about the use of DPP-4 inhibitors both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.